LPCAT3 deficiency reduces lipid absorption, thus reducing atherosclerogenic lipoproteins in the circulation 15, 25, 26. Intestinal LPCAT3 activity is required for a gut-brain feedback loop that couples absorption to food intake 25. LPCAT3 activity influences the biology and pathology of these tissues and plays an important role in lipoprotein production in the liver and small intestine 23, 24.
LPCAT3 is regulated by liver X receptor 21, a well-known factor in control of lipogenesis 22. Among them, LPCAT3 is the main isoform in major metabolic tissues, including the liver, small intestine, skeletal muscle, macrophage, and adipocyte 12, 14, 15, 16, 17, 18, 19, 20. Four lysophatidylcholine acyltransferases (LPCATs), LPCAT1–4, participate PC remodeling 9, 10, 11, 12, 13. Phosphatidylcholine (PC) is a major PL and its composition in mammalian cell membrane exhibits considerable structural diversity 7, 8.
So far, no structure has been resolved in this set of enzymes. The reacylation is catalyzed by lysophospholipid acyltransferase 5, 6. The asymmetrical distribution of fatty acids at the sn-1 and sn-2 positions is maintained in part by a deacylation-reacylation process first proposed by Lands 60 years ago (Lands’ Cycle or PL remodeling) 5, 6. PLs are synthesized de novo by the Kennedy pathway 4. Phospholipids (PLs) make up the major lipids in cellular membranes and in the circulation 1, 2, 3. The structural and functional analysis provides the basis for the re-acylation of lysophosphatidylcholine and the substrate preference during the reactions. A side pocket was found expanding the tunnel for the arachidonoyl CoA and holding the main body of arachidonoyl. A reaction chamber was revealed in the LPCAT3 structure where the lysophosphatidylcholine and arachidonoyl-CoA were positioned in two tunnels connected near to the catalytic center. Combining the x-ray crystallography and the cryo-electron microscopy, we determined the structures of LPCAT3 in apo-, acyl donor-bound, and acyl receptor-bound states.
The re-acylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT) and among the four LPCAT members in human, the LPCAT3 preferentially introduces polyunsaturated acyl onto the sn-2 position of lysophosphatidylcholine, thereby modulating the membrane fluidity and membrane protein functions therein. As the major component of cell membranes, phosphatidylcholine (PC) is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation remodeling via Lands’ cycle.
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